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Abstract:

Selected compounds are effective for prophylaxis and treatment of
diseases, such as HGF mediated diseases. The invention encompasses novel
compounds, analogs, prodrugs and pharmaceutically acceptable salts
thereof, pharmaceutical compositions and methods for prophylaxis and
treatment of diseases and other maladies or conditions involving, cancer
and the like. The subject invention also relates to processes for making
such compounds as well as to intermediates useful in such processes.

Claims:

1. A compound of Formula Ienantiomers, diastereomers, salts and solvates
thereof whereinA is absent or selected from phenyl, and 5-6 membered
heteroaryl;T is pyridyl, pyrimidinyl, pyrazinyl or napthyl any of which
may be optionally independently substituted with one or more halogen,
alkyl, haloalkyl, aryl, heteroaryl, --(CRaRb)n--SRa,
--(CRaRb)n--NRaR5, or
--(CRaRb)n--ORa;n is 0, 1, 2 or 3;Z is N or CR7
X is O, S, S(═O) or SO2 W is phenyl, benzomorpholinyl,
6-membered nitrogen containing heteroaryl, cycloalkyl or alkyl, any of
which may be optionally substituted with one more R3 groups;Ra
and Rb are each occurrence are independently H, alkyl, heterocyclo,
aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl,
cycloalkyl, cycloalkylalkyl, alkenyl and alkynylR1 and R2 are
each independently(1) H or(2) aryl, aralkyl, heteroaryl, heteroaralkyl,
heterocyclo, cycloalkyl, cycloalkenyl, alkylamino, alkyl, alkenyl, or
alkynyl any of which may be optionally substituted with one or more
R3 groups; or(3) R1 and R2 together with the nitrogen atom
to which they are bonded may combine to form a heterocyclo ring
optionally substituted with one or more R3 groups;R3 at each
occurrence is independently alkyl, halo, haloalkyl, hydroxy, alkoxy or
haloalkoxy;R4 is one or more substitutents independently selected at
each occurrence from H, cyano, hydroxyl, halo, heterocyclo optionally
substituted with one or more R3 groups,
--NRaC(═O)NRaR5, --OC(═O)NRaR5,
--NRaC(═O)OR5, --NRaC(═O)R5,
--SO2NRaR5, --SO2R5, --NRaSO2R5,
--NRaR5, alkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl,
phenylalkyl, heterocycloalkyl, alkoxy, haloalkoxy, alkylaminoalkoxy,
arylalkoxy, heterocycloalkoxy, cycloalkylalkoxy,
heterocyclo(hydroxyalkyl), cycloalkyl(hydroxyalkoxy),
aryl(hydroxyalkoxy), alkoxyalkoxy, aryloxyaloxy, heterocyclyloxyalkoxy,
cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, and cycloalkyloxy;R5
is H, alkyl, haloalkyl, arylalkyl, heterocyclylalkyl, cycloalkylalkyl,
aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, and
cycloalkyl;alternatively, where R5 is bonded to a nitrogen atom
together with R1, R5 and Ra together with the nitrogen
atom may combine to form a 3-6 membered heterocyclo ring optionally
independently substituted with one or more R3 groupsR6 is one
or more substitutents independently selected at each occurrence from H,
cyano, hydroxyl, halo, heterocyclo optionally substituted with one or
more R3 groups, --C(═O)NRaR5,
--OC(═O)NRaR5, --NRaC(═O)OR5,
--NRaC(═O)R5, --SO2NRaR5, --SO2R5,
--NRaSO2R5, --NRaR5, alkyl, aminoalkyl,
alkylaminoalkyl, alkoxyalkyl, arylalkyl, heterocycloalkyl, alkoxy,
haloalkoxy, alkylaminoalkoxy, arylalkoxy, heterocycloalkoxy,
cycloalkylalkoxy, heterocyclo(hydroxyalkoxy), cycloalkyl(hydroxyalkoxy),
ary(hydroxyalkoxy), aryloxyalkoxy, heterocyclyloxyalkoxy,
cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, cycloalkyloxy, aryl, and
heteroarylalternatively where R6 comprises an NRaR5
moeity, Ra and R5 together with the nitrogen atom to which they
are bonded may combine to form a 4-to-6 membered ring.

2. A compound of claim 1 wherein T is pyridyl, optionally independently
substituted with one or more halogen, alkyl, haloalkyl, aryl, heteroaryl,
--(CRaRb)n--SRa,
--(CRaRb)n--NRaR5, or
--(CRaRb)n--ORa.

3. A compound of claim 2 wherein W is phenyl optionally substituted with
one more R3 groups.

4. A compound of claim 2 having the structure of Formula IIwherein the T
pyridyl ring is optionally independently substituted with one or more
halogen, alkyl, haloalkyl, aryl, heteroaryl,
--(CRaRb)n--SRa,
--(CRaRb)n--NRaR5 or
--(CRaRb)n--ORa.

5. A compound of claim 4 having the structure of formula IIIwhere R3*
is independently selected from halogen, alkyl, haloalkyl, aryl,
heteroaryl, --(CRaRb)n--SRa,
--(CRaRb)n--NRaR5 or
--(CRaRb)n--ORa.

[0006]Various biological activities have been described for HGF through
interaction with c-met (Hepatocyte Growth Factor--Scatter Factor (HGF-SF)
and the c-Met Receptor, Goldberg and Rosen, eds., Birkhauser
Verlag-Basel, 67-79 (1993). The biological effect of HGF/SF may depend in
part on the target cell. HGF induces a spectrum of biological activities
in epithelial cells, including mitogenesis, stimulation of cell motility
and promotion of matrix invasion (Biochem. Biophys. Res. Comm.,
122:1450-1459 (1984); Proc. Natl. Acad. Sci. U.S.A., 88:415-419 (1991)).
It stimulates the motility and invasiveness of carcinoma cells, the
former having been implicated in the migration of cells required for
metastasis. HGF can also act as a "scatter factor", an activity that
promotes the dissociation of epithelial and vascular endothelial cells
(Nature, 327:239-242 (1987); J. Cell Biol., 111:2097-2108 (1990); EMBO
J., 10:2867-2878 (1991); Proc. Natl. Acad. Sci. USA, 90:649-653 (1993)).
Therefore, HGF is thought to be important in tumor invasion (Hepatocyte
Growth Factor-Scatter Factor (HGF-SF) and the C-Met Receptor, Goldberg
and Rosen, eds., Birkhauser Verlag-Basel, 131-165 (1993)).

[0007]HGF and c-Met are expressed at abnormally high levels in a large
variety of solid tumors. High levels of HGF and/or c-Met have been
observed in liver, breast, pancreas, lung, kidney, bladder, ovary, brain,
prostate, gallbladder and myeloma tumors in addition to many others. The
role of HGF/c-Met in metastasis has been investigated in mice using cell
lines transformed with HGF/c-Met (J. Mol. Med., 74:505-513 (1996)).
Overexpression of the c-Met oncogene has also been suggested to play a
role in the pathogenesis and progression of thyroid tumors derived from
follicular epithelium (Oncogene, 7:2549-2553 (1992)). HGF is a morphogen
(Development, 110:1271-1284 (1990); Cell, 66:697-711 (1991)) and a potent
angiogenic factor (J. Cell Biol., 119:629-641 (1992)).

[0008]Recent work on the relationship between inhibition of angiogenesis
and the suppression or reversion of tumor progression shows great promise
in the treatment of cancer (Nature, 390:404-407 (1997)), especially the
use of multiple angiogenesis inhibitors compared to the effect of a
single inhibitor. Angiogenesis can be stimulated by HGF, as well as
vascular endothelial growth factor (VEGF) and basic fibroblast growth
factor (bFGF).

[0009]Angiogenesis, the process of sprouting new blood vessels from
existing vasculature and arteriogenesis, the remodeling of small vessels
into larger conduit vessels are both physiologically important aspects of
vascular growth in adult tissues. These processes of vascular growth are
required for beneficial processes such as tissue repair, wound healing,
recovery from tissue ischemia and menstrual cycling. They are also
required for the development of pathological conditions such as the
growth of neoplasias, diabetic retinopathy, rheumatoid arthritis,
psoriasis, certain forms of macular degeneration, and certain
inflammatory pathologies. The inhibition of vascular growth in these
contexts has also shown beneficial effects in preclinical animal models.
For example, inhibition of angiogenesis by blocking vascular endothelial
growth factor or its receptor has resulted in inhibition of tumor growth
and in retinopathy. Also, the development of pathological pannus tissue
in rheumatoid arthritis involves angiogenesis and might be blocked by
inhibitors of angiogenesis.

[0010]The ability to stimulate vascular growth has potential utility for
treatment of ischemia-induced pathologies such as myocardial infarction,
coronary artery disease, peripheral vascular disease, and stroke. The
sprouting of new vessels and/or the expansion of small vessels in
ischemic tissues prevents ischemic tissue death and induces tissue
repair. Certain diseases are known to be associated with deregulated
angiogenesis, for example ocular neovascularization, such as
retinopathies (including diabetic retinopathy), age-related macular
degeneration, psoriasis, hemangioblastoma, hemangioma, arteriosclerosis,
inflammatory disease, such as a rheumatoid or rheumatic inflammatory
disease, especially arthritis (including rheumatoid arthritis), or other
chronic inflammatory disorders, such as chronic asthma, arterial or
post-transplantational atherosclerosis, endometriosis, and neoplastic
diseases, for example so-called solid tumors and liquid tumors (such as
leukemias). Treatment of malaria and related viral diseases may also be
mediated by HGF and cMet.

[0011]Elevated levels of HGF and c-Met have also been observed in
non-oncological settings, such as hypertension, myocardial infarction and
rheumatoid arthritis. It has been observed that levels of HGF increase in
the plasma of patients with hepatic failure (Gohda et al., supra) and in
the plasma (Hepatol., 13:734-750 (1991)) or serum (J. Biochem., 109:8-13
(1991)) of animals with experimentally induced liver damage. HGF has also
been shown to be a mitogen for certain cell types, including melanocytes,
renal tubular cells, keratinocytes, certain endothelial cells and cells
of epithelial origin (Biochem. Biophys. Res. Commun., 176:45-51 (1991);
Biochem. Biophys. Res. Commun., 174:831-838 (1991); Biochem.,
30:9768-9780 (1991); Proc. Natl. Acad. Sci. USA, 88:415-419 (1991)). Both
HGF and the c-Met proto-oncogene have been postulated to play a role in
microglial reactions to CNS injuries (Oncogene, 8:219-222 (1993)).

[0013]In view of the role of HGF and/or c-Met in potentiating or promoting
such diseases or pathological conditions, it would be useful to have a
means of substantially reducing or inhibiting one or more of the
biological effects of HGF and its receptor. Thus a compound that reduces
the effect of HGF would be a useful compound. Compounds of the current
invention have not been previously described as inhibitors of
angiogenesis such as for the treatment of cancer.

[0016]A class of compounds useful in treating cancer and angiogenesis is
defined by Formula I

enantiomers, diastereomers, salts and solvates thereof wherein [0017]A is
absent or selected from phenyl, and 5-6 membered heteroaryl; [0018]T is
pyridyl, pyrimidinyl, pyrazinyl or napthyl any of which may be optionally
independently substituted with one or more halogen, alkyl, haloalkyl,
aryl, heteroaryl, --(CRaRb)n--SRa,
--(CRaRb)n--NRaR5, or
--(CRaRb)n--ORa; [0019]n is 0, 1, 2 or 3; [0020]Z is
N or CR7[0021]X is O, S, S(═O) or SO2[0022]W is phenyl,
benzomorpholinyl, 6-membered nitrogen containing heteroaryl, cycloalkyl
or alkyl, any of which may be optionally substituted with one more
R3 groups; [0023]Ra and Rb are each occurrence are
independently H, alkyl, heterocyclo, aryl, heteroaryl, arylalkyl,
heteroarylalkyl, heterocycloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl
and alkynyl [0024]R1 and R2 are each independently [0025](1) H
or [0026](2) aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclo,
cycloalkyl, cycloalkenyl, alkylamino, alkyl, alkenyl, or alkynyl any of
which may be optionally substituted with one or more R3 groups; or
[0027](3) R1 and R2 together with the nitrogen atom to which
they are bonded may combine to form a heterocyclo ring optionally
substituted with one or more R3 groups; [0028]R3 at each
occurrence is independently alkyl, halo, haloalkyl, hydroxy, alkoxy or
haloalkoxy; [0029]R4 is one or more substitutents independently
selected at each occurrence from H, cyano, hydroxyl, halo, heterocyclo
optionally substituted with one or more R3 groups,
--NRaC(═O)NRaR5, --OC(═O)NRaR5,
--NRaC(═O)OR5, --NRaC(═O)R5,
--SO2NRaR5, --SO2R5, --NRaSO2R5,
--NRaR5, alkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl,
phenylalkyl, heterocycloalkyl, alkoxy, haloalkoxy, alkylaminoalkoxy,
arylalkoxy, heterocycloalkoxy, cycloalkylalkoxy,
heterocyclo(hydroxyalkyl), cycloalkyl(hydroxyalkoxy),
aryl(hydroxyalkoxy), alkoxyalkoxy, aryloxyaloxy, heterocyclyloxyalkoxy,
cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, and cycloalkyloxy;
[0030]R5 is H, alkyl, haloalkyl, arylalkyl, heterocyclylalkyl,
cycloalkylalkyl, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, and
cycloalkyl; [0031]alternatively, where R5 is bonded to a nitrogen
atom together with Ra, R5 and Ra together with the
nitrogen atom may combine to form a 3-6 membered heterocyclo ring
optionally independently substituted with one or more R3 groups
[0032]R6 is one or more substitutents independently selected at each
occurrence from H, cyano, hydroxyl, halo, heterocyclo optionally
substituted with one or more R3 groups, --C(═O)NRaR5,
--OC(═O)NRaR5, --NRaC(═O)OR5,
--NRaC(═O)R5, --SO2NRaR5, --SO2R5,
--NRaSO2R5, --NRaR5, alkyl, aminoalkyl,
alkylaminoalkyl, alkoxyalkyl, arylalkyl, heterocycloalkyl, alkoxy,
haloalkoxy, alkylaminoalkoxy, arylalkoxy, heterocycloalkoxy,
cycloalkylalkoxy, heterocyclo(hydroxyalkoxy), cycloalkyl(hydroxyalkoxy),
ary(hydroxyalkoxy), aryloxyalkoxy, heterocyclyloxyalkoxy,
cycloalkyloxyalkoxy, aryloxy, heterocyclyloxy, cycloalkyloxy, aryl, and
heteroaryl [0033]alternatively where R6 comprises an
NRaR5 moeity, Ra and R5 together with the nitrogen
atom to which they are bonded may combine to form a 4-to-6 membered ring.

[0034]Preferred compounds within the scope of Formula I include compounds
where the T ring is pyridyl, especially compounds of Formula II:

[0035]wherein the T pyridyl ring is optionally independently substituted
with one or more halogen, alkyl, haloalkyl, aryl, heteroaryl,
--(CRaRb)n--SRa,
--(CRaRb)n--NRaR5 or
--(CRaRb)n--ORa.

[0036]Preferred compounds within the scope of Formula II include compounds
where W is phenyl and ring A is absent, especially compounds of Formula
III

[0049]The invention also relates to pharmaceutical compositions containing
the above compounds, together with a pharmaceutically acceptable vehicle
or carrier.

[0050]The invention also relates to a method of treating cancer in a
subject using the above compounds.

[0051]The invention also relates to a method of reducing tumor size in a
subject using the above compounds.

[0052]The invention also relates to a method of reducing metastasis in a
tumor in a subject, using the above compounds.

[0053]The invention also relates to a method of treating HGF-mediated
disorders in a subject using the above compounds.

Indications

[0054]Compounds of the present invention would be useful for, but not
limited to, the prevention or treatment of angiogenesis related diseases.
The compounds of the invention have c-Met inhibitory activity. The
compounds of the invention are useful in therapy as antineoplasia agents
or to minimize deleterious effects of HGF.

[0056]Preferably, the compounds are useful for the treatment of neoplasia
selected from lung cancer, colon cancer and breast cancer.

[0057]The compounds also would be useful for treatment of opthalmological
conditions such as corneal graft rejection, ocular neovascularization,
retinal neovascularization including neovascularization following injury
or infection, diabetic retinopathy, retrolental fibroplasia and
neovascular glaucoma; retinal ischemia; vitreous hemorrhage; ulcerative
diseases such as gastric ulcer; pathological, but non-malignant,
conditions such as hemangiomas, including infantile hemaginomas,
angiofibroma of the nasopharynx and avascular necrosis of bone; and
disorders of the female reproductive system such as endometriosis. The
compounds are also useful for the treatment of edema, and conditions of
vascular hyperpermeability.

[0058]The compounds of the invention are useful in therapy of
proliferative diseases. These compounds can be used for the treatment of
an inflammatory rheumatoid or rheumatic disease, especially of
manifestations at the locomotor apparatus, such as various inflammatory
rheumatoid diseases, especially chronic polyarthritis including
rheumatoid arthritis, juvenile arthritis or psoriasis arthropathy;
paraneoplastic syndrome or tumor-induced inflammatory diseases, turbid
effusions, collagenosis, such as systemic Lupus erythematosus,
poly-myositis, dermato-myositis, systemic sclerodermia or mixed
collagenosis; postinfectious arthritis (where no living pathogenic
organism can be found at or in the affected part of the body),
seronegative spondylarthritis, such as spondylitis ankylosans;
vasculitis, sarcoidosis, or arthrosis; or further any combinations
thereof. An example of an inflammation related disorder is (a) synovial
inflammation, for example, synovitis, including any of the particular
forms of synovitis, in particular bursal synovitis and purulent
synovitis, as far as it is not crystal-induced. Such synovial
inflammation may for example, be consequential to or associated with
disease, e.g. arthritis, e.g. osteoarthritis, rheumatoid arthritis or
arthritis deformans. The present invention is further applicable to the
systemic treatment of inflammation, e.g. inflammatory diseases or
conditions, of the joints or locomotor apparatus in the region of the
tendon insertions and tendon sheaths. Such inflammation may be, for
example, consequential to or associated with disease or further (in a
broader sense of the invention) with surgical intervention, including, in
particular conditions such as insertion endopathy, myofasciale syndrome
and tendomyosis. The present invention is further especially applicable
to the treatment of inflammation, e.g. inflammatory disease or condition,
of connective tissues including dermatomyositis and myositis.

[0059]These compounds can be used as active agents against such disease
states as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial
angiogenesis, coronary and cerebral collaterals, ischemic limb
angiogenesis, wound healing, peptic ulcer Helicobacter related diseases,
fractures, cat scratch fever, rubeosis, neovascular glaucoma and
retinopathies such as those associated with diabetic retinopathy or
macular degeneration. In addition, some of these compounds can be used as
active agents against solid tumors, malignant ascites, hematopoietic
cancers and hyperproliferative disorders such as thyroid hyperplasia
(especially Grave's disease), and cysts (such as hypervascularity of
ovarian stroma, characteristic of polycystic ovarian syndrome
(Stein-Leventhal syndrome)) since such diseases require a proliferation
of blood vessel cells for growth and/or metastasis.

[0060]Further, some of these compounds can be used as active agents
against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic
and allergic inflammation, ovarian hyperstimulation syndrome, brain
tumor-associated cerebral edema, high-altitude, trauma or hypoxia induced
cerebral or pulmonary edema, ocular and macular edema, ascites, and other
diseases where vascular hyperpermeability, effusions, exudates, protein
extravasation, or edema is a manifestation of the disease. The compounds
will also be useful in treating disorders in which protein extravasation
leads to the deposition of fibrin and extracellular matrix, promoting
stromal proliferation (e.g. fibrosis, cirrhosis and carpal tunnel
syndrome).

[0061]The compounds of the present invention are also useful in the
treatment of ulcers including bacterial, fungal, Mooren ulcers and
ulcerative colitis.

[0064]The compounds of the present invention are also useful in the
treatment of cardiovascular conditions such as atherosclerosis,
restenosis, arteriosclerosis, vascular occlusion and carotid obstructive
disease.

[0065]The compounds of the present invention are also useful in the
treatment of cancer related indications such as solid tumors, sarcomas
(especially Ewing's sarcoma and osteosarcoma), retinoblastoma,
rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including
leukemia and lymphoma, tumor-induced pleural or pericardial effusions,
and malignant ascites.

[0066]The compounds of the present invention are also useful in the
treatment of diabetic conditions such as diabetic retinopathy and
microangiopathy.

[0067]The compounds of the present invention are also useful in the
reduction of blood flow in a tumor in a subject.

[0068]The compounds of the present invention are also useful in the
reduction of metastasis of a tumor in a subject.

[0069]The compounds of this invention may also act as inhibitors of other
protein kinases, e.g. tie-2, lck, src, fgf, c-Met, ron, ckit and ret, and
thus be effective in the treatment of diseases associated with other
protein kinases.

[0070]Besides being useful for human treatment, these compounds are also
useful for veterinary treatment of companion animals, exotic animals and
farm animals, including mammals, rodents, and the like. More preferred
animals include horses, dogs, and cats.

[0071]As used herein, the compounds of the present invention include the
pharmaceutically acceptable derivatives thereof.

[0072]Where the plural form is used for compounds, salts, and the like,
this is taken to mean also a single compound, salt and the like.

DEFINITIONS

[0073]Angiogenesis" is defined as any alteration of an existing vascular
bed or the formation of new vasculature, which benefits tissue pervasion.
This includes the formation of new vessels by sprouting of endothelial
cells from existing blood vessels or the remodeling of existing vessels
to alter size, maturity, direction or flow properties to improve blood
perfusion of tissue.

[0075]As used herein "c-Met" refers to the receptor for HGF. This includes
purified receptor, fragments of receptor, chemically synthesized
fragments of receptor, derivatives or mutated versions of receptor, and
fusion proteins comprising the receptor and another protein. "c-Met" as
used herein also includes the HGF receptor isolated from a species other
than humans.

[0077]As used herein "c-Met" refers to the receptor for HGF. This includes
purified receptor, fragments of receptor, chemically synthesized
fragments of receptor, derivatives or mutated versions of receptor, and
fusion proteins comprising the receptor and another protein. "c-Met" as
used herein also includes the HGF receptor isolated from a species other
than humans.

[0078]As used herein, the terms "hepatocyte growth factor" and "HGF" refer
to a growth factor typically having a structure with six domains (finger,
Kringle 1, Kringle 2, Kringle 3, Kringle 4 and serine protease domains).
Fragments of HGF constitute HGF with fewer domains and variants of HGF
may have some of the domains of HGF repeated; both are included if they
still retain their respective ability to bind a HGF receptor. The terms
"hepatocyte growth factor" and "HGF" include hepatocyte growth factor
from humans ("huHGF") and any non-human mammalian species, and in
particular rat HGF. The terms as used herein include mature, pre,
pre-pro, and pro forms, purified from a natural source, chemically
synthesized or recombinantly produced. Human HGF is encoded by the cDNA
sequence published by Miyazawa et al. (1989), supra, or Nakamura et al.
(1989), supra. The sequences reported by Miyazawa et al. and Nakamura et
al. differ in 14 amino acids. The reason for the differences is not
entirely clear; polymorphism or cloning artifacts are among the
possibilities. Both sequences are specifically encompassed by the
foregoing terms. It will be understood that natural allelic variations
exist and can occur among individuals, as demonstrated by one or more
amino acid differences in the amino acid sequence of each individual. The
terms "hepatocyte growth factor" and "HGF" specifically include the delta
5 huHGF as disclosed by Seki et al., supra.

[0079]The terms "HGF receptor" and "c-Met" when used herein refer to a
cellular receptor for HGF, which typically includes an extracellular
domain, a transmembrane domain and an intracellular domain, as well as
variants and fragments thereof which retain the ability to bind HGF. The
terms "HGF receptor" and "c-Met" include the polypeptide molecule that
comprises the full-length, native amino acid sequence encoded by the gene
variously known as p190MET. The present definition specifically
encompasses soluble forms of HGF receptor, and HGF receptor from natural
sources, synthetically produced in vitro or obtained by genetic
manipulation including methods of recombinant DNA technology. The HGF
receptor variants or fragments preferably share at least about 65%
sequence homology, and more preferably at least about 75% sequence
homology with any domain of the human c-Met amino acid sequence published
in Rodrigues et al., Mol. Cell. Biol., 11:2962-2970 (1991); Park et al.,
Proc. Natl. Acad. Sci., 84:6379-6383 (1987); or Ponzetto et al.,
Oncogene, 6:553-559 (1991).

[0080]The terms "agonist" and "agonistic" when used herein refer to or
describe a molecule which is capable of, directly or indirectly,
substantially inducing, promoting or enhancing HGF biological activity or
HGF receptor activation.

[0081]The terms "cancer" and "cancerous" when used herein refer to or
describe the physiological condition in mammals that is typically
characterized by unregulated cell growth. Examples of cancer include but
are not limited to, carcinoma, lymphoma, sarcoma, blastoma and leukemia.
More particular examples of such cancers include squamous cell carcinoma,
lung cancer, pancreatic cancer, cervical cancer, bladder cancer,
hepatoma, breast cancer, colon carcinoma, and head and neck cancer. While
the term "cancer" as used herein is not limited to any one specific form
of the disease, it is believed that the methods of the invention will be
particularly effective for cancers which are found to be accompanied by
increased levels of HGF or expression of c-Met in the mammal.

[0083]The term "mammal" as used herein refers to any mammal classified as
a mammal, including humans, cows, horses, dogs and cats. In a preferred
embodiment of the invention, the mammal is a human.

[0084]Given that elevated levels of c-Met and HGF are observed in
hypertension, arteriosclerosis, myocardial infarction, and rheumatoid
arthritis, nucleic acid ligands will serve as useful therapeutic agents
for these diseases.

[0085]The term "treatment" includes therapeutic treatment as well as
prophylactic treatment (either preventing the onset of disorders
altogether or delaying the onset of a pre-clinically evident stage of
disorders in individuals).

[0086]A "pharmaceutically-acceptable derivative" denotes any salt, ester
of a compound of this invention, or any other compound which upon
administration to a patient is capable of providing (directly or
indirectly) a compound of this invention, or a metabolite or residue
thereof, characterized by the ability to inhibit angiogenesis.

[0087]The phrase "therapeutically-effective" is intended to qualify the
amount of each agent, which will achieve the goal of improvement in
disorder severity and the frequency of incidence over treatment of each
agent by itself, while avoiding adverse side effects typically associated
with alternative therapies. For example, effective neoplastic therapeutic
agents prolong the survivability of the patient, inhibit the rapidly
proliferating cell growth associated with the neoplasm, or effect a
regression of the neoplasm.

[0088]The term "H" denotes a single hydrogen atom. This radical may be
attached, for example, to an oxygen atom to form a hydroxyl radical.

[0089]Where the term "alkyl" is used, either alone or within other terms
such as "haloalkyl" and "alkylamino", it embraces linear or branched
radicals having one to about twelve carbon atoms. More preferred alkyl
radicals are "lower alkyl" radicals having one to about six carbon atoms.
Examples of such radicals include methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the
like. Even more preferred are lower alkyl radicals having one or two
carbon atoms. The term "alkylenyl" embraces bridging divalent alkyl
radicals such as methylenyl and ethylenyl. The term "lower alkyl
substituted with R2" does not include an acetal moiety.

[0090]The term "alkenyl" embraces linear or branched radicals having at
least one carbon-carbon double bond of two to about twelve carbon atoms.
More preferred alkenyl radicals are "lower alkenyl" radicals having two
to about six carbon atoms. Most preferred lower alkenyl radicals are
radicals having two to about four carbon atoms. Examples of alkenyl
radicals include ethenyl, propenyl, allyl, propenyl, butenyl and
4-methylbutenyl. The terms "alkenyl" and "lower alkenyl", embrace
radicals having "cis" and "trans" orientations, or alternatively, "E" and
"Z" orientations.

[0091]The term "alkynyl" denotes linear or branched radicals having at
least one carbon-carbon triple bond and having two to about twelve carbon
atoms. More preferred alkynyl radicals are "lower alkynyl" radicals
having two to about six carbon atoms. Most preferred are lower alkynyl
radicals having two to about four carbon atoms. Examples of such radicals
include propargyl, butynyl, and the like.

[0092]The term "halo" means halogens such as fluorine, chlorine, bromine
or iodine atoms.

[0093]The term "haloalkyl" embraces radicals wherein any one or more of
the alkyl carbon atoms is substituted with halo as defined above.
Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl
radicals including perhaloalkyl. A monohaloalkyl radical, for one
example, may have either an iodo, bromo, chloro or fluoro atom within the
radical. Dihalo and polyhaloalkyl radicals may have two or more of the
same halo atoms or a combination of different halo radicals. "Lower
haloalkyl" embraces radicals having 1-6 carbon atoms. Even more preferred
are lower haloalkyl radicals having one to three carbon atoms. Examples
of haloalkyl radicals include fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,
dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and
dichloropropyl. "Perfluoroalkyl" means alkyl radicals having all hydrogen
atoms replaced with fluoro atoms. Examples include trifluoromethyl and
pentafluoroethyl.

[0094]The term "hydroxyalkyl" embraces linear or branched alkyl radicals
having one to about ten carbon atoms any one of which may be substituted
with one or more hydroxyl radicals. More preferred hydroxyalkyl radicals
are "lower hydroxyalkyl" radicals having one to six carbon atoms and one
or more hydroxyl radicals. Examples of such radicals include
hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and
hydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals having
one to three carbon atoms.

[0095]The term "alkoxy" embraces linear or branched oxy-containing
radicals each having alkyl portions of one to about ten carbon atoms.
More preferred alkoxy radicals are "lower alkoxy" radicals having one to
six carbon atoms. Examples of such radicals include methoxy, ethoxy,
propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxy
radicals having one to three carbon atoms. Alkoxy radicals may be further
substituted with one or more halo atoms, such as fluoro, chloro or bromo,
to provide "haloalkoxy" radicals. Even more preferred are lower
haloalkoxy radicals having one to three carbon atoms. Examples of such
radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,
trifluoroethoxy, fluoroethoxy and fluoropropoxy.

[0096]The term "aryl", alone or in combination, means a carbocyclic
aromatic system containing one or two rings wherein such rings may be
attached together in a fused manner. The term "aryl" embraces aromatic
radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl, and
indanyl. More preferred aryl is phenyl. Said "aryl" group may have 1 to 3
substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro,
cyano, alkoxy and lower alkylamino. Phenyl substituted with
--O--CH2--O-- forms the aryl benzodioxolyl substituent.

[0097]The term "heterocyclyl" (or "heterocyclo") embraces saturated,
partially saturated and unsaturated heteroatom-containing ring radicals,
where the heteroatoms may be selected from nitrogen, sulfur and oxygen.
It does not include rings containing --O--O--, --O--S-- or --S--S--
portions. Said "heterocyclyl" group may have 1 to 3 substituents such as
hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo,
lower alkoxy, amino and lower alkylamino.

[0105]The term "alkylaminosulfonyl" includes "N-alkylaminosulfonyl" where
sulfamyl radicals are independently substituted with one or two alkyl
radical(s). More preferred alkylaminosulfonyl radicals are "lower
alkylaminosulfonyl" radicals having one to six carbon atoms. Even more
preferred are lower alkylaminosulfonyl radicals having one to three
carbon atoms. Examples of such lower alkylaminosulfonyl radicals include
N-methylaminosulfonyl, and N-ethylaminosulfonyl.

[0106]The terms "carboxy" or "carboxyl", whether used alone or with other
terms, such as "carboxyalkyl", denotes --CO2H.

[0107]The term "carbonyl", whether used alone or with other terms, such as
"aminocarbonyl", denotes --(C═O)--.

[0108]The term "aminocarbonyl" denotes an amide group of the formula
--C(═O)NH2.

[0109]The terms "N-alkylaminocarbonyl" and "N,N-dialkylaminocarbonyl"
denote aminocarbonyl radicals independently substituted with one or two
alkyl radicals, respectively. More preferred are "lower
alkylaminocarbonyl" having lower alkyl radicals as described above
attached to an aminocarbonyl radical.

[0110]The terms "N-arylaminocarbonyl" and "N-alkyl-N-arylaminocarbonyl"
denote aminocarbonyl radicals substituted, respectively, with one aryl
radical, or one alkyl and one aryl radical.

[0111]The terms "heterocyclylalkylenyl" and "heterocyclylalkyl" embrace
heterocyclic-substituted alkyl radicals. More preferred heterocyclylalkyl
radicals are "5- or 6-membered heteroarylalkyl" radicals having alkyl
portions of one to six carbon atoms and a 5- or 6-membered heteroaryl
radical. Even more preferred are lower heteroarylalkylenyl radicals
having alkyl portions of one to three carbon atoms. Examples include such
radicals as pyridylmethyl and thienylmethyl.

[0112]The term "aralkyl" embraces aryl-substituted alkyl radicals.
Preferable aralkyl radicals are "lower aralkyl" radicals having aryl
radicals attached to alkyl radicals having one to six carbon atoms. Even
more preferred are "phenylalkylenyl" attached to alkyl portions having
one to three carbon atoms. Examples of such radicals include benzyl,
diphenylmethyl and phenylethyl. The aryl in said aralkyl may be
additionally substituted with halo, alkyl, alkoxy, halkoalkyl and
haloalkoxy.

[0113]The term "alkylthio" embraces radicals containing a linear or
branched alkyl radical, of one to ten carbon atoms, attached to a
divalent sulfur atom. Even more preferred are lower alkylthio radicals
having one to three carbon atoms. An example of "alkylthio" is
methylthio, (CH3S--).

[0114]The term "haloalkylthio" embraces radicals containing a haloalkyl
radical, of one to ten carbon atoms, attached to a divalent sulfur atom.
Even more preferred are lower haloalkylthio radicals having one to three
carbon atoms. An example of "haloalkylthio" is trifluoromethylthio.

[0115]The term "alkylamino" embraces "N-alkylamino" and "N,N-dialkylamino"
where amino groups are independently substituted with one alkyl radical
and with two alkyl radicals, respectively. More preferred alkylamino
radicals are "lower alkylamino" radicals having one or two alkyl radicals
of one to six carbon atoms, attached to a nitrogen atom. Even more
preferred are lower alkylamino radicals having one to three carbon atoms.
Suitable alkylamino radicals may be mono or dialkylamino such as
N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the
like.

[0116]The term "arylamino" denotes amino groups, which have been
substituted with one or two aryl radicals, such as N-phenylamino. The
arylamino radicals may be further substituted on the aryl ring portion of
the radical.

[0117]The term "heteroarylamino" denotes amino groups, which have been
substituted with one or two heteroaryl radicals, such as N-thienylamino.
The "heteroarylamino" radicals may be further substituted on the
heteroaryl ring portion of the radical.

[0118]The term "aralkylamino" denotes amino groups, which have been
substituted with one or two aralkyl radicals. More preferred are
phenyl-C1-C3-alkylamino radicals, such as N-benzylamino. The
aralkylamino radicals may be further substituted on the aryl ring
portion.

[0119]The terms "N-alkyl-N-arylamino" and "N-aralkyl-N-alkylamino" denote
amino groups, which have been independently substituted with one aralkyl
and one alkyl radical, or one aryl and one alkyl radical, respectively,
to an amino group.

[0120]The term "aminoalkyl" embraces linear or branched alkyl radicals
having one to about ten carbon atoms any one of which may be substituted
with one or more amino radicals. More preferred aminoalkyl radicals are
"lower aminoalkyl" radicals having one to six carbon atoms and one or
more amino radicals. Examples of such radicals include aminomethyl,
aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferred
are lower aminoalkyl radicals having one to three carbon atoms.

[0121]The term "alkylaminoalkyl" embraces alkyl radicals substituted with
alkylamino radicals. More preferred alkylaminoalkyl radicals are "lower
alkylaminoalkyl" radicals having alkyl radicals of one to six carbon
atoms. Even more preferred are lower alkylaminoalkyl radicals having
alkyl radicals of one to three carbon atoms. Suitable alkylaminoalkyl
radicals may be mono or dialkyl substituted, such as N-methylaminomethyl,
N,N-dimethyl-aminoethyl, N,N-diethylaminomethyl and the like.

[0122]The term "alkylaminoalkoxy" embraces alkoxy radicals substituted
with alkylamino radicals. More preferred alkylaminoalkoxy radicals are
"lower alkylaminoalkoxy" radicals having alkoxy radicals of one to six
carbon atoms. Even more preferred are lower alkylaminoalkoxy radicals
having alkyl radicals of one to three carbon atoms. Suitable
alkylaminoalkoxy radicals may be mono or dialkyl substituted, such as
N-methylaminoethoxy, N,N-dimethylaminoethoxy, N,N-diethylaminoethoxy and
the like.

[0123]The term "alkylaminoalkoxyalkoxy" embraces alkoxy radicals
substituted with alkylaminoalkoxy radicals. More preferred
alkylaminoalkoxyalkoxy radicals are "lower alkylaminoalkoxyalkoxy"
radicals having alkoxy radicals of one to six carbon atoms. Even more
preferred are lower alkylaminoalkoxyalkoxy radicals having alkyl radicals
of one to three carbon atoms. Suitable alkylaminoalkoxyalkoxy radicals
may be mono or dialkyl substituted, such as N-methylaminomethoxyethoxy,
N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy,
N,N-diethylaminomethoxymethoxy and the like.

[0124]The term "carboxyalkyl" embraces linear or branched alkyl radicals
having one to about ten carbon atoms any one of which may be substituted
with one or more carboxy radicals. More preferred carboxyalkyl radicals
are "lower carboxyalkyl" radicals having one to six carbon atoms and one
carboxy radical. Examples of such radicals include carboxymethyl,
carboxypropyl, and the like. Even more preferred are lower carboxyalkyl
radicals having one to three CH2 groups.

[0125]The term "halosulfonyl" embraces sulfonyl radicals substituted with
a halogen radical. Examples of such halosulfonyl radicals include
chlorosulfonyl and fluorosulfonyl.

[0126]The term "arylthio" embraces aryl radicals of six to ten carbon
atoms, attached to a divalent sulfur atom. An example of "arylthio" is
phenylthio.

[0127]The term "aralkylthio" embraces aralkyl radicals as described above,
attached to a divalent sulfur atom. More preferred are
phenyl-C1-C3-alkylthio radicals. An example of "aralkylthio" is
benzylthio.

[0128]The term "aryloxy" embraces optionally substituted aryl radicals, as
defined above, attached to an oxygen atom. Examples of such radicals
include phenoxy.

[0129]The term "aralkoxy" embraces oxy-containing aralkyl radicals
attached through an oxygen atom to other radicals. More preferred
aralkoxy radicals are "lower aralkoxy" radicals having optionally
substituted phenyl radicals attached to lower alkoxy radical as described
above.

[0133]The term "cycloalkylalkyl" embraces cycloalkyl-substituted alkyl
radicals. Preferable cycloalkylalkyl radicals are "lower cycloalkylalkyl"
radicals having cycloalkyl radicals attached to alkyl radicals having one
to six carbon atoms. Even more preferred are "5-6-membered
cycloalkylalkyl" attached to alkyl portions having one to three carbon
atoms. Examples of such radicals include cyclohexylmethyl. The cycloalkyl
in said radicals may be additionally substituted with halo, alkyl, alkoxy
and hydroxy.

[0134]The term "cycloalkenyl" includes carbocyclic groups having one or
more carbon-carbon double bonds including "cycloalkyldienyl" compounds.
Preferred cycloalkenyl groups include C3-C6 rings. More
preferred compounds include, for example, cyclopentenyl,
cyclopentadienyl, cyclohexenyl and cycloheptadienyl.

[0135]The term "comprising" is meant to be open ended, including the
indicated component but not excluding other elements.

[0136]The term "Formulas I through VII" includes any sub formulas.

[0137]The compounds of the invention are endowed with c-Met inhibitory
activity.

[0138]The present invention also comprises the use of a compound of the
invention, or pharmaceutically acceptable salt thereof, in the
manufacture of a medicament for the treatment either acutely or
chronically of an angiogenesis mediated disease state, including those
described previously. The compounds of the present invention are useful
in the manufacture of an anti-cancer medicament. The compounds of the
present invention are also useful in the manufacture of a medicament to
attenuate or prevent disorders through inhibition of c-Met.

[0139]The present invention comprises a pharmaceutical composition
comprising a therapeutically effective amount of a compound of Formulas
I, through VII in association with a least one pharmaceutically
acceptable carrier, adjuvant or diluent.

[0140]The present invention also comprises a method of treating
angiogenesis related disorders in a subject having or susceptible to such
disorder, the method comprising treating the subject with a
therapeutically effective amount of a compound of Formula I, through VII.

Combinations

[0141]While the compounds of the invention can be administered as the sole
active pharmaceutical agent, they can also be used in combination with
one or more compounds of the invention or other agents. When administered
as a combination, the therapeutic agents can be formulated as separate
compositions that are administered at the same time or sequentially at
different times, or the therapeutic agents can be given as a single
composition.

[0142]The phrase "co-therapy" (or "combination-therapy"), in defining use
of a compound of the present invention and another pharmaceutical agent,
is intended to embrace administration of each agent in a sequential
manner in a regimen that will provide beneficial effects of the drug
combination, and is intended as well to embrace co-administration of
these agents in a substantially simultaneous manner, such as in a single
capsule having a fixed ratio of these active agents or in multiple,
separate capsules for each agent.

[0143]Specifically, the administration of compounds of the present
invention may be in conjunction with additional therapies known to those
skilled in the art in the prevention or treatment of neoplasia, such as
with radiation therapy or with cytostatic or cytotoxic agents.

[0144]If formulated as a fixed dose, such combination products employ the
compounds of this invention within the accepted dosage ranges. Compounds
of Formula I through VII may also be administered sequentially with known
anticancer or cytotoxic agents when a combination formulation is
inappropriate. The invention is not limited in the sequence of
administration; compounds of the invention may be administered either
prior to, simultaneous with or after administration of the known
anticancer or cytotoxic agent.

[0146]There are large numbers of antineoplastic agents available in
commercial use, in clinical evaluation and in pre-clinical development,
which would be selected for treatment of neoplasia by combination drug
chemotherapy. Such antineoplastic agents fall into several major
categories, namely, antibiotic-type agents, alkylating agents,
antimetabolite agents, hormonal agents, immunological agents,
interferon-type agents and a category of miscellaneous agents.

[0187]In some embodiments, the combination comprises a composition of the
present invention in combination with at least one anti-angiogenic agent.
Agents are inclusive of, but not limited to, in vitro synthetically
prepared chemical compositions, antibodies, antigen binding regions,
radionuclides, and combinations and conjugates thereof. An agent can be
an agonist, antagonist, allosteric modulator, toxin or, more generally,
may act to inhibit or stimulate its target (e.g., receptor or enzyme
activation or inhibition), and thereby promote cell death or arrest cell
growth.

[0188]Exemplary anti-tumor agents include HERCEPTN® (trastuzumab),
which may be used to treat breast cancer and other forms of cancer, and
RITUXAN® (rituximab), ZEVALIN® (ibritumomab tiuxetan), and
LYMPHOCIDE® (epratuzumab), which may be used to treat non-Hodgkin's
lymphoma and other forms of cancer, GLEEVAC® which may be used to
treat chronic myeloid leukemia and gastrointestinal stromal tumors, and
BEXXAR® (iodine 131 tositumomab) which may be used for treatment of
non-Hodgkins's lymphoma.

[0192]Alternatively, the present compounds may also be used in
co-therapies with other anti-neoplastic agents, such as VEGF antagonists,
other kinase inhibitors including p38 inhibitors, KDR inhibitors, EGF
inhibitors and CDK inhibitors, TNF inhibitors, metallomatrix proteases
inhibitors (MMP), COX-2 inhibitors including celecoxib, NSAID's, or
αvβ3 inhibitors.

[0193]The present invention comprises processes for the preparation of a
compound of Formulas I through VII. Also included in the family of
compounds of Formula I through VII are the pharmaceutically acceptable
salts thereof. The term "pharmaceutically-acceptable salts" embraces
salts commonly used to form alkali metal salts and to form addition salts
of free acids or free bases. The nature of the salt is not critical,
provided that it is pharmaceutically acceptable. Suitable
pharmaceutically acceptable acid addition salts of compounds of Formulas
I through VII may be prepared from an inorganic acid or from an organic
acid. Examples of such inorganic acids are hydrochloric, hydrobromic,
hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriate
organic acids may be selected from aliphatic, cycloaliphatic, aromatic,
arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic
acids, example of which are formic, acetic, adipic, butyric, propionic,
succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,
glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,
anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic
(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,
benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,
sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,
digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,
glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,
nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic, persulfuric,
2-phenylpropionic, picric, pivalic propionic, succinic, tartaric,
thiocyanic, mesylic, undecanoic, stearic, algenic, β-hydroxybutyric,
salicylic, galactaric and galacturonic acid. Suitable
pharmaceutically-acceptable base addition salts of compounds of Formulas
I through VII include metallic salts, such as salts made from aluminum,
calcium, lithium, magnesium, potassium, sodium and zinc, or salts made
from organic bases including primary, secondary and tertiary amines,
substituted amines including cyclic amines, such as caffeine, arginine,
diethylamine, N-ethyl piperidine, aistidine, glucamine, isopropylamine,
lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,
triethylamine, trimethylamine. All of these salts may be prepared by
conventional means from the corresponding compound of the invention by
reacting, for example, the appropriate acid or base with the compound of
Formulas I through VII. When a basic group and an acid group are present
in the same molecule, a compound of Formulas I through VII may also form
internal salts.

General Synthetic Procedures

[0194]The compounds of the invention can be synthesized according to the
following procedures of Schemes 1-10, wherein the substituents are as
defined for Formulas I through VII above, except where further noted.

[0195]The following abbreviations are used throughout the specification:

[0203]5-bromo-2-(3-fluoro-4-methoxyphenylamino)-N-phenylnicotinamide (657
mg, 1578 μmol) was suspended in HOAc (1 ml) and hydrobromic acid (48%,
3.1 ml, 57087 μmol) was added. The flask was fitted with reflux
condenser and placed in a preheated oil bath (115° C.-120°
C.) and stirred. When LCMS indicated the starting material had been
consumed, the reaction cooled to room temperature, and the pH of the
aqueous phase was adjusted to 5, first with 5 N NaOH, and then with 10%
aqueous HCl.

[0206]5-bromo-2-(3-fluoro-4-hydroxyphenylamino)-N-phenylnicotinamide (57.8
mg, 144 μmol) and tetrakis(triphenylphosphine)palladium (19.2 mg, 17
μmol) were dissolved in THF (1.5 ml) and methylzinc chloride (0.18 ml,
˜2 M in THF, 360 μmol) was added. The flask was fitted with a
reflux condenser and put in a preheated oil bath (70C) and stirred under
nitrogen. After 30 minutes, the reaction was cooled to room temperature
and quenched with saturated ammonium chloride (1 ml) and 0.5 M EDTA (1
ml) and allowed to stand at room temperature overnight.

[0207]In a separate flask,
5-bromo-2-(3-fluoro-4-hydroxyphenylamino)-N-phenylnicotinamide (1.71 g,
4.25 mmol) and tetrakis(triphenylphosphine)palladium (445 mg, 0.385 mmol)
were dissolved in THF (20 ml) and methylzinc chloride (5.5 ml, ˜2 M
in THF, 11 mmol) was added via syringe. The flask was fitted with a
reflux condenser and placed in a preheated oil bath (70°
C.-81° C.) and stirred under nitrogen. After 2 hours and 20
minutes, more Pd(PPh3)4 (331 mg, 0.286 mmol) and methylzinc
chloride (4.1 ml, ˜2 M in THF, 8.2 mmol) were added, and stirring
was continued at 70C for another hour. The reaction was cooled to room
temperature and quenched with saturated ammonium chloride (15 ml) and 0.5
M EDTA (20 ml).

[0208]Both reactions were combined, the layers were separated, and the
aqueous phase was extracted with EtOAc one time. Then, the organic phase
was washed with 1 N NaOH and then with 5 N NaOH. The aqueous washings
(with pH of 12) were combined and washed with DCM. Then, the pH of the
aqueous phase was adjusted to around 8 with concentrated HCl, and then
extracted with DCM and 10:1 DCM/MeOH). The organic extracts were
combined, dried over sodium sulfate, filtered, concentrated, and filtered
through silica gel (˜2 inches, EtOAc) to afford a mixture of the
desired 2-(3-fluoro-4-hydroxyphenylamino)-5-methyl-N-phenylnicotinamide
and the corresponding des-methyl analog. This mixture was taken on to the
next step.

[0210]365 mg of a mixture of
2-(3-fluoro-4-hydroxyphenylamino)-5-methyl-N-phenylnicotinamide and the
des-methyl analog and 4-chloropyridin-2-amine (264 mg, 2054 μmol) were
dissolved in NMP (5.0 ml) and triethylamine (0.75 ml, 5381 μmol) was
added. The flask was fitted with a reflux condenser, placed in a
preheated oil bath (185° C.-190° C.), and stirred under
argon. After about 22 hours, more 4-chloropyridin-2-amine (250 mg, 1.95
mmol), DMAP (171 mg, 1.40 mmol), triethylamine (0.30 ml, 4.1 mmol), and
NMP (1 ml) were added, and stirring was continued at 190C for another
day. The reaction was then cooled to room temperature and quenched with
water (20 ml). The water was decanted, and the residual solid was
collected with DCM and MeOH, concentrated, and purified on silica gel
(50:1->25:1 DCM/MeOH->15:1 DCM/2 N ammonia in MeOH) to afford the
desired 2-(4-(2-aminopyridine-4-yloxy)-3-fluorophenylamino)-5-methyl-N-ph-
enylnicotinamide along with the des-methyl analog. This mixture was taken
to the last step.

[0212]264 mg of a mixture of
2-(4-(2-aminopyridine-4-yloxy)-3-fluorophenylamino)-5-methyl-N-phenylnico-
tinamide and the des-methyl analog was dissolved in THF (4.9 ml) and
triethylamine (0.20 ml, 1.4 mmol) and then phenyl chloroformate (0.16 ml,
1.3 mmol) were added. The reaction was stirred at room temperature, and
then morpholine (0.60 ml, 6.90 mmol) was added after 30 minutes. The
reaction was stirred at room temperature overnight, and then more
morpholine (0.45 ml, 5.2 mmol) was added, and the flask was fitted with a
reflux condenser and placed in an oil bath and heated to 70° C.

[0273]A mixture of
N-(4-(4-amino-2-fluorophenoxy)pyridin-2-yl)pyrrolidine-1-carboxamide
(0.158 g, 0.5 mmol), ethyl
4-chloro-2-(methylthio)pyrimidine-5-carboxylate (0.2 g, 1.0 mmol),
N-ethyl-N-isopropylpropan-2-amine (0.1 g, 1.0 mmol) in 1,4-dioxane (1 g,
11 mmol) was heated in microwave (CEM) at 60 W and 60° C. for 40
min. The resultant was diluted with DCM (15 mL) and water (10 mL). The
organic layer was separated, dried over sodium sulfate, and concentrated.
The residue was used for the next step without further purification.

[0274]Step 2.
4-(3-fluoro-4-(2-(pyrrolidine-1-carboxamido)pyridin-4-yloxy)phenylamino)--
2-(methylthio)-N-phenylpyrimidin-5-carboxamide. To a solution of ethyl
4-(3-fluoro-4-(2-(pyrrolidine-1-carboxamido)pyridin-4-yloxy)phenylamino)--
2-(methylthio)pyrimidine-5-carboxylate (0.15 g, 0.29 mmol) in ethanol
(10.0 g, 217 mmol) was added aq. 1N sodium hydroxide (1 mL, 1 mmol). The
resultant was stirred for 16 h at RT: 71648-22-99. Then, the mixture was
concentrated and diluted with water and washed with diethyl ether (10
mL). The aqueous layer was neutralized with aq. 2 N HCl and extrated with
DCM (20 mL×3). The combined organic solution was dried over sodium
sulfate and concentrated. The residue was used for the next step without
further purification.

[0283]The title compound was prepared similar to the procedures described
in example 30. MS (ESI pos. ion) m/z: 582 (MH+). Calc'd exact mass for
C28H23F4N7O3: 581.

[0284]Formulas I through VII may be demonstrated in vivo. The
pharmacological properties of the compounds of this invention may be
confirmed by a number of pharmacological in vitro assays. The exemplified
pharmacological assays, which follow have been carried out with the
compounds according to the invention and their salts.

Biological Testing

[0285]The efficacy of the compounds of the invention as inhibitors of HGF
related activity is demonstrated as follows.

c-Met Receptor Assay

[0286]Cloning, Expression and Purification of c-Met Kinase Domain

[0287]A PCR product covering residues 1058-1365 of c-Met (c-Met kinase
domain) is generated as described in WO 06/116,713 the entirety of which
is incorporated herein by reference.

Alternative Purification of Human GST-cMET from Baculovirus Cells

[0288]Baculovirus cells are broken in 5× (volume/weight) of Lysis
Buffer (50 mM HEPES, pH 8.0, 0.25 M NaCl, 5 mM mercaptoethanol, 10%
glycerol plus Complete Protease Inhibitors (Roche (#10019600), 1 tablet
per 50 mL buffer). The lysed cell suspension is centrifuged at
100,000×g (29,300 rpm) in a Beckman ultracentrifuge Ti45 rotor for
1 h. The supernatant is incubated with 10 ml of Glutathione Sepharose 4B
from Amersham Biosciences (#27-4574-01). Incubation is carried out
overnight in a cold room (approximately 8° C.). The resin and
supernatant is poured into an appropriately sized disposable column and
the flow through supernatant was collected. The resin is washed with 10
column volumes (100 mL) of Lysis Buffer. The GST-cMET is eluted with 45
mL of 10 mM Glutathione (Sigma #G-4251) in Lysis Buffer. The elution is
collected as 15 mL fractions. Aliquots of the elution fractions are run
on SDS PAGE (12% Tris Glycine gel, Invitrogen, #EC6005BOX). The gel is
stained with 0.25% Coomassie Blue stain. Fractions with GST-cMET are
concentrated with a Vivaspin 20 mL Concentrator (#VS2002; 10.00 MW
cutoff) to a final volume less than 2.0 ml. The concentrated GST-cMET
solution is applied to a Superdex 75 16/60 column (Amersham Biosciences
#17-1068-01) equilibrated with 25 mM Tris, pH 7.5, 100 mM NaCl, 10 mM
mercaptoethanol, 10% glycerol. The GST-cMET is eluted with an isocratic
run of the above buffer, with the eluent collected in 1.0 mL fractions.
Fractions with significant OD280 readings are run on another 12%
Tris Glycine gel. The peak tubes with GST-cMET are pooled and the
OD280 is read with the column buffer listed above as the blank
buffer.

[0289]Phosphorylation of the purified GST-cMET is performed by incubating
the protein for 3 h at RT with the following:

[0290]After incubation, the solution is concentrated in a Vivaspin 20 ml
Concentrator to a volume less than 2.00 ml. The solution is applied to
the same Superdex 75 16/60 column used above after re-equilibration. The
GST-cMET is eluted as described above. The elution fractions
corresponding to the first eluted peak on the chromatogram are run on a
12% Tris Glycine gel, as above, to identify the fractions with GST-cMET.
Fractions are pooled and the OD280 is read with the column buffer
used as the blank.

[0311]Nitro-cellulose disk preparation: The tip of a 20-gauge needle was
cut off square and beveled with emery paper to create a punch. This tip
was then used to cut out ≈0.5 mm diameter disks from a
nitrocellulose filter paper sheet (Gelman Sciences). Prepared disks were
then placed into Eppendorf microfuge tubes containing solutions of either
0.1% BSA in PBS vehicle, 10 μM rHu-VEGF (R&D Systems, Minneapolis,
Minn.), or 3.75 μM rHu-bFGF (R&D Systems, Minneapolis, Minn.) and
allowed to soak for 45-60 min before use. Each nitrocellulose filter disk
absorbs approximately 0.1 μL of solution.

Tumor Model

[0312]A431 cells (ATCC) are expanded in culture, harvested and injected
subcutaneously into 5-8 week old female nude mice (CD1 nu/nu, Charles
River Labs) (n=5-15). Subsequent administration of compound by oral
gavage (10-200 mpk/dose) begins anywhere from day 0 to day 29 post tumor
cell challenge and generally continues either once or twice a day for the
duration of the experiment. Progression of tumor growth is followed by
three dimensional caliper measurements and recorded as a function of
time. Initial statistical analysis is done by repeated measures analysis
of variance (RMANOVA), followed by Scheffe post hoc testing for multiple
comparisons. Vehicle alone (Ora-Plus, pH 2.0) is the negative control.

Tumor Models

[0313]Human glioma tumor cells (U87MG cells, ATCC) are expanded in
culture, harvested and injected subcutaneously into 5-8 week old female
nude mice (CD1 nu/nu, Charles River Labs) (n=10). Subsequent
administration of compound by oral gavage or by IP (10-100 mpk/dose)
begins anywhere from day 0 to day 29 post tumor cell challenge and
generally continues either once or twice a day for the duration of the
experiment. Progression of tumor growth is followed by three dimensional
caliper measurements and recorded as a function of time. Initial
statistical analysis is done by repeated measures analysis of variance
(RMANOVA), followed by Scheffe post hoc testing for multiple comparisons.
Vehicle alone (captisol, or the like) is the negative control.

[0314]Human gastric adenocarcinoma tumor cells (MKN45 cells, ATCC) are
expanded in culture, harvested and injected subcutaneously into 5-8 week
old female nude mice (CD1 nu/nu, Charles River Labs) (n=10). Subsequent
administration of compound by oral gavage or by IP (10-100 mpk/dose)
begins anywhere from day 0 to day 29 post tumor cell challenge and
generally continues either once or twice a day for the duration of the
experiment. Progression of tumor growth is followed by three dimensional
caliper measurements and recorded as a function of time. Initial
statistical analysis is done by repeated measures analysis of variance
(RMANOVA), followed by Scheffe post hoc testing for multiple comparisons.
Vehicle alone (captisol, or the like) is the negative control

[0315]The compounds exemplified herein have been assayed and inhibit c-Met
with Kis in a range from 0.2 nm to 576 nm. Illustrative activity
values are provided in the following table.

[0316]Also embraced within this invention is a class of pharmaceutical
compositions comprising the active compounds of Formulas I through VII in
association with one or more non-toxic, pharmaceutically-acceptable
carriers and/or diluents and/or adjuvants (collectively referred to
herein as "carrier" materials) and, if desired, other active ingredients.
The active compounds of the present invention may be administered by any
suitable route, preferably in the form of a pharmaceutical composition
adapted to such a route, and in a dose effective for the treatment
intended. The compounds and compositions of the present invention may,
for example, be administered orally, mucosally, topically, rectally,
pulmonarily such as by inhalation spray, or parentally including
intravascularly, intravenously, intraperitoneally, subcutaneously,
intramuscularly intrasternally and infusion techniques, in dosage unit
formulations containing conventional pharmaceutically acceptable
carriers, adjuvants, and vehicles.

[0317]The pharmaceutically active compounds of this invention can be
processed in accordance with conventional methods of pharmacy to produce
medicinal agents for administration to patients, including humans and
other mammals.

[0318]For oral administration, the pharmaceutical composition may be in
the form of, for example, a tablet, capsule, suspension or liquid. The
pharmaceutical composition is preferably made in the form of a dosage
unit containing a particular amount of the active ingredient. Examples of
such dosage units are tablets or capsules. For example, these may contain
an amount of active ingredient from about 1 to 2000 mg, preferably from
about 1 to 500 mg. A suitable daily dose for a human or other mammal may
vary widely depending on the condition of the patient and other factors,
but, once again, can be determined using routine methods.

[0319]The amount of compounds which are administered and the dosage
regimen for treating a disease condition with the compounds and/or
compositions of this invention depends on a variety of factors, including
the age, weight, sex and medical condition of the subject, the type of
disease, the severity of the disease, the route and frequency of
administration, and the particular compound employed. Thus, the dosage
regimen may vary widely, but can be determined routinely using standard
methods. A daily dose of about 0.01 to 500 mg/kg, preferably between
about 0.01 and about 50 mg/kg, and more preferably about 0.01 and about
30 mg/kg body weight may be appropriate. The daily dose can be
administered in one to four doses per day.

[0320]For therapeutic purposes, the active compounds of this invention are
ordinarily combined with one or more adjuvants appropriate to the
indicated route of administration. If administered per os, the compounds
may be admixed with lactose, sucrose, starch powder, cellulose esters of
alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium
stearate, magnesium oxide, sodium and calcium salts of phosphoric and
sulfuric acids, gelatin, acacia gum, sodium alginate,
polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or
encapsulated for convenient administration. Such capsules or tablets may
contain a controlled-release formulation as may be provided in a
dispersion of active compound in hydroxypropylmethyl cellulose.

[0321]In the case of psoriasis and other skin conditions, it may be
preferable to apply a topical preparation of compounds of this invention
to the affected area two to four times a day.

[0322]Formulations suitable for topical administration include liquid or
semi-liquid preparations suitable for penetration through the skin (e.g.,
liniments, lotions, ointments, creams, or pastes) and drops suitable for
administration to the eye, ear, or nose. A suitable topical dose of
active ingredient of a compound of the invention is 0.1 mg to 150 mg
administered one to four, preferably one or two times daily. For topical
administration, the active ingredient may comprise from 0.001% to 10%
w/w, e.g., from 1% to 2% by weight of the formulation, although it may
comprise as much as 10% w/w, but preferably not more than 5% w/w, and
more preferably from 0.1% to 1% of the formulation.

[0323]When formulated in an ointment, the active ingredients may be
employed with either paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients may be formulated in a cream with
an oil-in-water cream base. If desired, the aqueous phase of the cream
base may include, for example at least 30% w/w of a polyhydric alcohol
such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol,
polyethylene glycol and mixtures thereof. The topical formulation may
desirably include a compound, which enhances absorption or penetration of
the active ingredient through the skin or other affected areas. Examples
of such dermal penetration enhancers include DMSO and related analogs.

[0324]The compounds of this invention can also be administered by a
transdermal device. Preferably transdermal administration will be
accomplished using a patch either of the reservoir and porous membrane
type or of a solid matrix variety. In either case, the active agent is
delivered continuously from the reservoir or microcapsules through a
membrane into the active agent permeable adhesive, which is in contact
with the skin or mucosa of the recipient. If the active agent is absorbed
through the skin, a controlled and predetermined flow of the active agent
is administered to the recipient. In the case of microcapsules, the
encapsulating agent may also function as the membrane.

[0325]The oily phase of the emulsions of this invention may be constituted
from known ingredients in a known manner. While the phase may comprise
merely an emulsifier, it may comprise a mixture of at least one
emulsifier with a fat or an oil or with both a fat and an oil.
Preferably, a hydrophilic emulsifier is included together with a
lipophilic emulsifier, which acts as a stabilizer. It is also preferred
to include both an oil and a fat. Together, the emulsifier(s) with or
without stabilizer(s) make-up the so-called emulsifying wax, and the wax
together with the oil and fat make up the so-called emulsifying ointment
base, which forms the oily dispersed phase of the cream formulations.
Emulsifiers and emulsion stabilizers suitable for use in the formulation
of the present invention include Tween 60, Span 80, cetostearyl alcohol,
myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl
distearate alone or with a wax, or other materials well known in the art.

[0326]The choice of suitable oils or fats for the formulation is based on
achieving the desired cosmetic properties, since the solubility of the
active compound in most oils likely to be used in pharmaceutical emulsion
formulations is very low. Thus, the cream should preferably be a
non-greasy, non-staining and washable product with suitable consistency
to avoid leakage from tubes or other containers. Straight or branched
chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl
stearate, propylene glycol diester of coconut fatty acids, isopropyl
myristate, decyl oleate, isopropyl palmitate, butyl stearate,
2-ethylhexyl palmitate or a blend of branched chain esters may be used.
These may be used alone or in combination depending on the properties
required. Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be used.

[0327]Formulations suitable for topical administration to the eye also
include eye drops wherein the active ingredients are dissolved or
suspended in suitable carrier, especially an aqueous solvent for the
active ingredients. The active ingredients are preferably present in such
formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%
and particularly about 1.5% w/w.

[0328]Formulations for parenteral administration may be in the form of
aqueous or non-aqueous isotonic sterile injection solutions or
suspensions. These solutions and

[0333]Although the pharmacological properties of the compounds of Formulas
I through VII vary with structural change, in general, activity possessed
by compounds of suspensions may be prepared from sterile powders or
granules using one or more of the carriers or diluents mentioned for use
in the formulations for oral administration or by using other suitable
dispersing or wetting agents and suspending agents. The compounds may be
dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn
oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium
chloride, tragacanth gum, and/or various buffers. Other adjuvants and
modes of administration are well and widely known in the pharmaceutical
art. The active ingredient may also be administered by injection as a
composition with suitable carriers including saline, dextrose, or water,
or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.
propylene glycol) or micellar solubilization (ie. Tween 80).

[0334]The sterile injectable preparation may also be a sterile injectable
solution or suspension in a non-toxic parenterally acceptable diluent or
solvent, for example as a solution in 1,3-butanediol. Among the
acceptable vehicles and solvents that may be employed are water, Ringer's
solution, and isotonic sodium chloride solution. In addition, sterile,
fixed oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil may be employed, including synthetic
mono- or diglycerides. In addition, fatty acids such as oleic acid find
use in the preparation of injectables.

[0335]For pulmonary administration, the pharmaceutical composition may be
administered in the form of an aerosol or with an inhaler including dry
powder aerosol.

[0336]Suppositories for rectal administration of the drug can be prepared
by mixing the drug with a suitable non-irritating excipient such as cocoa
butter and polyethylene glycols that are solid at ordinary temperatures
but liquid at the rectal temperature and will therefore melt in the
rectum and release the drug.

[0337]The pharmaceutical compositions may be subjected to conventional
pharmaceutical operations such as sterilization and/or may contain
conventional adjuvants, such as preservatives, stabilizers, wetting
agents, emulsifiers, buffers etc. Tablets and pills can additionally be
prepared with enteric coatings. Such compositions may also comprise
adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

[0338]The foregoing is merely illustrative of the invention and is not
intended to limit the invention to the disclosed compounds. Variations
and changes, which are obvious to one skilled in the art are intended to
be within the scope and nature of the invention, which are defined, in
the appended claims.

[0339]From the foregoing description, one skilled in the art can easily
ascertain the essential characteristics of this invention, and without
departing from the spirit and scope thereof, can make various changes and
modifications of the invention to adapt it to various usages and
conditions.

[0340]No unacceptable toxicological effects are expected when compounds of
the present invention are administered in accordance with the present
invention.

[0341]All mentioned references, patents, applications and publications,
are hereby incorporated by reference in their entirety, as if here
written.

Patent applications by Elizabeth Rainbeau, Port Hueneme, CA US

Patent applications by Jean-Christophe Harmange, Andover, MA US

Patent applications by Julie Germain, Quebec CA

Patent applications by Mark H. Norman, Thousand Oaks, CA US

Patent applications by Matthew Lee, Calabasas, CA US

Patent applications by Ning Xi, Thousand Oaks, CA US

Patent applications by Noel D'Angelo, Thousand Oaks, CA US

Patent applications by Shimin Xu, Newbury Park, CA US

Patent applications by Shon Booker, Thousand Oaks, CA US

Patent applications by Steven Bellon, Wellesley, MA US

Patent applications by Tae-Seong Kim, Thousand Oaks, CA US

Patent applications by Amgen Inc.

Patent applications in class The additional hetero ring is attached indirectly to the morpholine ring by an acyclic chain having a hetero atom as a chain member

Patent applications in all subclasses The additional hetero ring is attached indirectly to the morpholine ring by an acyclic chain having a hetero atom as a chain member